Method of supplementing the diet and ameliorating oxidative stress

ABSTRACT

A method of supplementing a diet and ameliorating oxidative stress in a mammal includes administering a pharmaceutically effective amount of an active compound having the chemical structure: 
     
       
         
         
             
             
         
       
     
     where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.

This document is a continuation of U.S. patent application Ser. No.12/630,259 filed on Dec. 3, 2009, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/201,060 filed on Dec. 6,2008, the full disclosures of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates generally to the field of dietarysupplements for mammals and, more particularly, to methods ofsupplementing a diet, removing heavy metals and other toxins andameliorating oxidative stress.

BACKGROUND OF THE INVENTION

Heavy metals such as mercury, lead, cadmium and silver can bind toproteins on the proteins' incorporated cysteine residues which containsulfhydryl or —SH groups. This abnormally inhibits or activates theirbiological properties. Further, a heavy metal binding specific proteinscan induce damage that leads to overproduction or leakage of reactiveoxygen species (ROSs) from their normal locations. These ROSs, mostlyproduced in the mitochondria of the cells of the body, then react withprotein, nucleic acid (DNA, RNA) and lipid molecules in the healthy cellchanging their property/chemistry and leading to unhealthy cells thatmay die or at least be unable to defend themselves from other stressfactors such as viral infection. In addition to heavy metals there aremany other chemical toxicants that can induce oxidative stressincluding, for example, radiation toxicity, acetominophin and dioxin.Further, it is well known that the oxidation of reduced glutathione(GSH) to oxidized glutathione (G-S-S-G) is one of the first biochemicalsignals for apoptotic cell death (or programmed cell death). Theinadvertent oxidation of GSH by toxin produced ROSs could lead toincreased GSSG and cell death also.

In order to medically prevent or reduce the problem, heavy metals mustbe excreted by natural means or complexed by medically based chelatorcompounds that render them biologically unavailable to elicit theirtoxic effects. To effect this removal and tightly bind the heavy metals,the treating compound must be able to effectively remove the metal fromthe single sulfur residue and bind it more tightly than is capable withonly one sulfur to metal bond. That is, the compound must make more thanone sulfur to metal bond to be able to prevent subsequent reaction orexchange of the complexed metal with other biomolecules. Additionally,the ideal chelating compound must have degrees of freedom of rotation ofthe sulfur bonds to be able to bind different heavy metals that havedifferent coordination chemistries (e.g. different bond angles thatconfer tighter bonding). For example, Hg²⁺ and Pb²⁺ both can form twobonds with —SH groups, but the most stable binding of each metal wouldhave different bond angles.

To be effective at treating both intracellular heavy metal toxicity andradiation toxicity as well as oxidative stress associated therewith, thetreating compound has to be able to cross the cellular membrane withefficiency and, if the brain is involved, the treating compound must beable to cross the blood brain barrier. In order to be able to do thisthe compound has to be quite hydrophobic in nature in order to be ableto pass through the lipid bilayer of the cell membrane to reach the siteof heavy metal binding and intercept the ROS produced by themitochondria before they react and damage cellular constituents.Further, the ideal treating compound must be of very low toxicity tocells and not disrupt membranes or biological pathways. In addition, thetreating compound must be efficiently excreted from all tissues of thebody in a non-toxic form. For example, if the treating compound bindsmercury cation (Hg²⁺) it must carry this metal ion out of the body andnot distribute it to other organs such as the kidney.

The ideal treatment compound must also exhibit stability to airoxidation and breakdown so that the treating compound can be effectivelystored and packaged for delivery to the patient in original, activeform. The treating compound ideally must also be suited for ease ofadministration to a patient. Further, the treating compound must notdeplete the body of essential metals such as zinc and copper. Inaddition, it should also have an adequately long plasma half-life suchthat it is possible to take eight hours rest and not have the treatingcompound significantly depleted from the plasma and tissues.

The present invention relates to methods of supplementing the diet of amammal, removing heavy metals and other toxins from a mammal andameliorating undesirable oxidative stress in a mammal.

SUMMARY OF THE INVENTION

In accordance with the purposes of the present invention as describedherein, a method of supplementing a diet of a mammal is provided. Thatmethod comprises: administering to said mammal a pharmaceuticallyeffective amount of a compound having a chemical formula:

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium.

In accordance with yet another aspect of the present invention, a methodto remove heavy metals and toxins from a mammal comprises: administeringto said mammal a pharmaceutically effective amount of a compound havinga chemical formula:

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium.

In accordance with yet another aspect of the present invention a methodis provided for relieving oxidative stress in a mammal. That methodcomprises: administering to said mammal a pharmaceutically effectiveamount of a compound having a chemical formula:

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium.

In the following description there is shown and described severaldifferent embodiments of the invention, simply by way of illustration ofsome of the modes best suited to carry out the invention. As it will berealized, the invention is capable of other different embodiments andits several details are capable of modification in various, obviousaspects all without departing from the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention relates to various methods of supplementing thediet of a mammal, removing heavy metals and other toxins from a mammaland relieving or ameliorating oxidative stress in a mammal. Each of themethods relies upon administering to said mammal a pharmaceuticallyeffective amount of a compound having a chemical formula:

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium. The activecompounds and their synthesis are described in detail in issued U.S.Pat. No. 6,586,600 to Atwood et al, the full disclosure of which isincorporated herein by reference.

While U.S. Pat. No. 6,586,600 discloses use of the compounds in questionfor removing heavy metals from the environment such as the natural watersupply, it provides no teaching or suggestion that the compounds couldbe utilized in mammals as a dietary supplement, to ameliorate oxidativestress, to raise in vivo glutathione levels or to treat heavy metal orother toxicity. In fact, the compounds in U.S. Pat. No. 6,586,600 weremostly ineffective at treating environmental contaminations of heavymetal due to their insolubility in water and many organic solvents. Theconventional wisdom is that any metal chelator has to be water solubleto be effective is evidenced by the currently known chelators such asdimercapopropane sulfonate (DMPS), dimercaptosuccinic acid (DMSA),ethylenediaminetetraacetic acid (EDTA) and even the natural mammalianheavy metal chelator glutathione. These observations made the use of thecompounds questionable for any mammalian based treatment regarding theremoval of charged toxic metals like Hg²⁺, Pb²⁺, and Cd²⁺ which arewater soluble and would most likely be located in the aqueous aspects ofmammalian tissues. Additionally, any compound that is not water solublenor soluble in most organic solvents would not be expected to pass theintestinal endothelial membrane barrier and enter the blood and tissuesof the mammal. Further, the compound(s) would have to cross the cellmembrane to be able to interact with and bind the intracellular locatedheavy metal responsible for the toxic effects. It would also have to beable to cross the blood brain barrier to be effective for any neurotoxicheavy metal effect. Then the excretion of the chelator-metal complex andthe resulting toxicity of this complex would have to be effective andnot cause any toxic effects. The disclosure in U.S. Pat. No. 6,586,600suggests none of these desired performance parameters.

The pharmaceutically effective amount of the compounds in question maybe administered in any appropriate manner including, but not limited to,oral administration, transdermal administration, nasal administration,intravenous administration and administration by suppository. The methodof supplementing a diet of a mammal includes administering between about0.5 and about 40.0 mg of the compound per kilogram of the mammal's totalbody weight per day although, due to the lack of toxicity higher doselevels are acceptable. The compound may be administered in combinationwith another antioxidant or chelator. That antioxidant may be selectedfrom a group including but not limited to vitamin-E, vitamin-D,cysteine, cystine, glutathione, lipoic acid and combinations thereof. Inone particularly useful embodiment the compound has the chemical formula

In the method of removing heavy metals and other toxins from a mammal,the compound is administered in an amount between about 0.5 and about60.0 mg per kilogram of the mammal's total body weight per day. In thismethod the compound may be administered with a water soluble metalchelator. That water soluble metal chelator may be selected from a groupconsisting of glutathione (GSH), dihydrolipoic acid (DLPA), lipoic acid(LPA), N-acetylcysteine (NAC), dimercaptopropane sulfonate (DMPS),dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA),and mixtures thereof. It should be appreciated, however, that otherwater soluble metal chelators besides those listed could be utilized.

In the method of relieving oxidative stress in a mammal the compound maybe administered orally, transdermally, nasally, intravenously, bysuppository and other appropriate. Typically the compound isadministered in an amount of between about 0.5 and about 100.0 mg of thecompound per kilogram of the mammal's total body weight per day. Theexceptionally low level of mammalian toxicity would also allow higherdoses to be used in cases of acute toxicity or high oxidative stress.Here, it should also be noted that the present method may be used totreat oxidative stress resulting from virtually any cause or sourceincluding, but not limited to, heavy metal toxicity, drugs such asacetaminophen, xenobiotics, aging, infection, physical injury anddisease.

These compounds are not used to directly produce intracellularglutathione and work primarily by salvaging naturally produced reducedglutathione (GSH) by the process of scavenging the intracellular ROSspreventing the oxidation to oxidized glutathione (GSSG). Also, theinhibitory binding of Hg²⁺ and Pb²⁺ and their removal from enzymeinvolved in the synthesis (e.g. glutatmine synthetase) and recovery ofGSH (e.g. glutathione reductase) would additionally aid in the recoveryof GSH to optimal levels. In accordance with an additional aspect of thepresent invention the compound may be administered with a precursor ofglutathione. That glutathione precursor may be selected from a group ofprecursors consisting of cysteine, glycene, glutamate and combinationsthereof.

In yet another possible embodiment the compound is administered with adietary supplement that supports glutathione synthesis. Such dietarysupplements include, but are not limited to, whey protein,N-acetylcysteine, cysteine, glutathione, nicotine adenine dinucleotide(NAD⁺), reduced nicotine adenine dinucleotide (NADH), glycylcysteine(gly-cyc) glutamylcysteine (glu-cys), and combinations thereof. In oneparticularly useful embodiment the compound used for relieving oxidativestress has the chemical formula

The compounds used in the present invention provide a number of uniquebenefits that make them attractive for use in methods of (a)supplementing the diet, (b) removing heavy metals and other toxins and(c) ameliorating oxidative stress in mammals. The compounds, andparticularly, the compound

known as N,N′-bis(2-mercaptoethyl)isophthalamide or OSR, exhibit verylow if any toxicity and do not adversely affect commonly usedblood/urine tests commonly used to measure human health.

More specifically, OSR is without toxicity when administered in testanimals at levels up to 5,000 mg per day. In fact, OSR is so non-toxicthat an LD-50 could not be identified and was established as greaterthan 5 grams per kilogram body weight.

Advantageously OSR is lipid soluble and, accordingly, after entering theplasma can enter cells of all tissues, cross the blood brain barrier andenter the bone marrow. This is important because the damage caused byheavy metals and the oxidative stress produced by hydroxyl free radicalsand other free radicals of the reactive oxygen species mostly occur inthe intracellular space. In contrast, most dietary antioxidants arewater soluble and cannot enter into cells effectively nor can they crossthe blood/brain barrier.

As a further advantage, the lipid solubility of OSR increases the timeit spends in the body allowing it to be more effective at chelatingheavy metals and scavenging hydroxyl free radicals. The half-life of OSRin plasma of test animals was about six to seven hours whereas mostwater soluble antioxidants and chelators, such as resveratrol, DMPS,DMSA, and glutathione have a half-life of less than one to two hours asthey are rapidly cleared by the kidneys or liver as they do not enterthe cells and remain in the plasma.

It should also be appreciated that OSR is a pure compound that is notused as a substrate in any synthetic biochemical pathway of mammals. Assuch it does not disrupt any biochemical process. It simply partitionsinto the hydrophobic areas, binds heavy metals, reacts with freeradicals eliminating them and is then excreted from the body primarilythrough the biliary transport system of the liver. It is also importantto note that the two component parts of OSR consists of naturally,non-toxic, occurring benzoates and a catabolic product of cysteinemetabolism that are combined to produce a product that has very low ifany toxicity.

As should be appreciated from the following table, OSR has anexceptionally high ORAC (oxygen-radical-absorbance-capacity) score.

Compound Score (μmole TE/100 g) OSR#1 192,400 Acai 18,500 Dark Chocolate13,120 Pomegranates 3,307 Blueberries 2,400 Garlic 1,939 Cranberries1,750 Spinach 1,260 Broccoli Florets 890 Kiwi Fruit 610

The ORAC score is measured by a compound or elixer's ability tointercept reactive oxygen species, free radicals preventing them fromoxidizing a water soluble fluorescent vitamin-E derivative. OSR has theability in the body to protect vitamin-E (a fat soluble vitamin) andother fat soluble natural compounds such as lipids from damage byoxidizing free radicals since it partitions into the hydrophobic areaswhere they exist and reacts with free radicals more effectively thanthey do, thereby scavenging the hydroxyl free radicals and preventingthem from doing damage. Significantly, vitamin-E has been recommendedfor Alzheimer's diseased subjects to prevent oxidizing damage to theirbrain membranes or membrane lipids due to vitamin-E's reactivity withhydroxyl free radicals. OSR is more capable of reacting with theseradicals than vitamin-E and, accordingly, OSR should provide even betterprotection. In fact, OSR should salvage vitamin E and D in vivo.

Additionally, it is significant to note that when OSR is takenregularly, it does significantly increase the reduced (GSH) overoxidized (GSSG) glutathione ratio and increases total glutathione in thewhole blood. Thus, more glutathione is available to scavenge freeradicals and participate in the P-450 system to remove insoluble organictoxins from the membranes and cells. Thus, the body is better able tomaintain a healthy glutathione level when the diet of the mammal issupplemented with OSR or other compounds of the present invention.

OSR has also been shown to bind injected mercury from mercury chlorideand render this mercury non-toxic. Rats injected with 1-5 levels (orhigher) of lethal doses of mercury chloride were protected from death bya single 10-fold excess above the mercury level of OSR dissolved inDMSO.

Rats given a 0.6 lethal dose of mercury chloride were protected frommercury induced toxic effects (blood in urine and feces, death, weightloss, ataxia) when given a 10-fold excess of OSR twenty-thirty minuteslater. After five days, the mercury levels of many organs known to bemercury sensitive was measured. A toxic level of mercury still existedin the OSR treated rats but no toxic effects could be detected whereasthe rats not given OSR showed these toxic effects. The OSR bound mercurywas shown to be primarily excreted through the fecal route at a rateconsistent with the P-450 system being involved.

OSR also has excellent stability when stored in sealed plastic testtubes with less than three percent breakdown occurring at sixteen monthsof storage at room temperature. Most antioxidants break down veryrapidly when exposed to air or water but OSR is exceptional in thisregards.

OSR also has only a very low odor level, much lower than most othersulfhyrdryl containing dietary compounds. Advantageously, thischaracteristic makes OSR more palatable for oral administration.

OSR also has an exceptionally high affinity for mercury, lead, arsenicand cadmium. Although OSR has good affinitive for the essential elementsof copper, iron and zinc it seems as if the respective binding proteinsof the body bind them tighter and treatment with OSR does not result ina significant lowering of these essential elements. Also, copper andzinc are primarily found in a water environment (hydrophilic aspects) ofthe body whereas OSR partitions into the hydrophobic aspects. Thisseparation may play a role in the lack of OSR removing copper and zinc.However, in diseases with excess free copper, iron or zinc, OSR islikely to be able to bind and decrease the toxicity of these metals.

A kinetic study of OSR shows that it crosses the blood brain barrier,enters the intercellular space of all tissues tested which places OSR inthe vicinity of the mitochondria and the cytoplasm. The mitochondria,especially if abnormal or damaged by heavy metals or radiation, are themain producers of the free radicals that cause cellular damage to themembranes, proteins or nucleic acids (DNA, RNA). Therefore, OSR ispositioned to intercept these free radicals before they do damage andthe ORAC scores show us OSR is exceptional at scavenging these toxicchemicals. Thus, OSR operates as an antioxidant in a more efficient andeffective level than antioxidants generally known in the art.

It should also be appreciated that OSR is cleared from all tissuestested by over 90% twenty-four hours after ingestion. Therefore, notoxic build-up of OSR occurs in the mammal.

OSR also has a reactive site available for oxidation by the P-450enzymes which allow OSR to be oxidized and modified as a sulfated,glycosylated or glutathione modified derivative by natural processes.

At the same time, OSR is better than glutathione delivered by IV ortransdermally for increasing the intracellular level of glutathione. Therational behind this is based on the very low level of glutathione foundin the plasma versus the intracellular levels which are 1,000 to 10,000times higher. Any glutathione molecule that enters the blood by IV ortransdermal delivery would be immediately bound and removed by theglutathione receptors in the liver that take glutathione labeled toxinsout of the plasma and place them in the bile (bilary transport system).Glutathione in the blood would not remain long enough to enter cellswhere it could be used, plus it would have to enter in the face of asignificant concentration gradient that would prevent this. Thisstatement is based on the fact that many water insoluble toxicants areremoved from the body by first oxidizing them, attaching glutathione (bythe enzyme glutathione-s-transferase) to this oxidized site on thetoxin, then actively transporting the glutathione labeled toxicant outof the cell and into the blood where it is removed by the glutathionereceptors of the bileary transport system. In contrast, OSR enters allcells and due to its hydrophobic nature, inserts in some degree into thelipid membrane or other hydrophobic sites where it can scavenge hydroxylfree radicals, the major chemical species that oxidize glutathione andcause its levels to drop. OSR salvages naturally produced glutathioneintracellularly enhancing its longevity and raising glutathione levelsin vivo without having to battle transport across a membrane against ahigh gradient of glutathione.

Pharmaceutical compositions of the present invention may be prepared bycombining a pharmaceutical effective amount of a compound having achemical formula

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium, with anexcipient. Substantially any suitable excipient may be utilizedincluding but not limited to albumin, almond oil, ascorbic acid, benzoicacid, calcium stearate, canola oil, calcium carboxymethylcellulose,sodium carboxymethylcellulose, castor oil, hydrogenated castor oil,microcrystalline cellulose, corn oil, cotton seed oil, cyclodextrins,ethylene glycol palmitostearate, gelatin, glycerin, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,low-substituted hydroxypropyl cellulose, lanolin, linoleic acid,magnesium silicate, magnesium stearate, medium-chain triglycerides,mineral oil, olive oil, peanut oil, pectin, compressible sugar,sunflower oil, hydrogenated vegetable oil and water. In order to providemultiple antioxidant potential, the pharmaceutical compositions mayfurther include other antioxidants including, but not limited tovitamin-E, vitamin-D, cystine, glutathione, lipoic acid and combinationsthereof. Further the pharmaceutical compositions may include a watersoluble metal chelator to enhance removal of toxic metals both throughthe liver and kidney and with an enhanced rate. Substantially, anysuitable water soluble metal chelator may be utilized including but notlimited to glutathione (GSH), dihydrolipoic acid (DLPA), lipoic acid(LPA), N-acetylcysteine (NAC), dimercaptopropane sulfonate (DMPS),dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA),and mixtures thereof. Further, in order to further enhance the levels ofglutathione in the subject, the pharmaceutical compositions may includea precursor of glutathione which may be selected from a group includingbut not limited to cysteine, glycine, glutamate and combinationsthereof. Further pharmaceutical compositions may include a dietarysupplement that supports glutathione synthesis. Substantially anyappropriate dietary supplement that supports glutathione synthesis maybe utilized including but not limited to whey protein, N-acetylcystein,cysteine, glutathione, nicotine adenine dinucleotide (NAD⁺), reducednicotine adenine dinucleotide (NADH), glycylcysteine (gly-cys),glutamylcysteine (glu-cyc), and combinations thereof. Pharmaceuticalcompositions may also include various binders, preservatives, mineralsupplements, bulking agents, diluents, carriers, flavoring agents thatare widely known to be used in pharmaceutical compositions. Exemplarypharmaceutical compositions include between about 95.5 and about 85weight percent active compound, between about 0.5 and about 15 weightpercent excipient. The optional additional antioxidant(s) may beprovided at between about 0 and about 50 weight percent. The optionaladditional water soluble metal chelator may be provided at between about0 and about 20 weight percent. The optional additional precursor ofglutathione may be provided at between about 0 and about 50 weightpercent. Further the optionally additional dietary supplement thatsupports glutathione synthesis may be provided at between about 0 andabout 50 weight percent. One or more of any of the optional additivesmay be included. The optional additive replaces a like percentage of thecompound in the final composition.

Preferred dosage forms for oral administration include the isolatedcompounds in powder form. Such powders may be taken up with a swoop andspread onto food or mixed into drinks for easy consumption without badtaste. The pure compounds may be pre-mixed with certain dietaryingredients such as butter, olive oil, corn oil, albumin, whey or otherfoods which will help in absorption of the compounds by the mere processof dissolving them. Using OSR dissolved in corn oil, it was determinedthat it takes two hours post ingestion for the maximum level of OSR toshow up in the plasma of all tested animals. Further, after 24 hourspost-ingestion the OSR levels were shown to drop between 4-12% of thepeak values seen at hour 2.

Some of the commercially available solubilizers that can be used forparenteral (injectible), oral, topical or intranasal delivery indifferent combinations and ratios according to need include: (a)co-solvents such as polyethylene glycol 300/400, Macrogol 300/400,Lutrol E300/E400, propylene glycol, Soluphor P and NMP; (b) PEGderivatives such as Cremophor RH40, Cremophor EL/ELP and Solutol HS-15;and (c) polyoxamers such as Lutrol F68, Lutrol F127, Lutrol Micro 68 andLutrol Micro 127.

The pure compound may be encapsulated in several weight forms (eg. 50,100, 200, 500 mg/capsule) and taken orally. The pure compound may bemixed with excipients (eg. microcrystalline cellulose, hypermellose,magnesium stearate) to provide a mixed material that can be efficientlyencapsulated by machines for mass production at a rapid rate.

The pure compound may also be made into tablet form by mixing withcommon agents or binders used to induce adhesive properties for tabletformation.

OSR and any of the other hydrophobic compounds may be dissolved insimple oils and applied to the skin. The compounds dissolved in DMSO(dimethylsulfoxide) are rapidly taken up through the skin without localirritation.

OSR and the other compounds may be placed in suppository capsules eitherin powder form or dissolved in oils or as mixed with protein basedmaterial (eg. human serum albumin) for delivery. OSR and the othercompounds may also be dissolved in human serum albumin for intravenousdelivery. Similarly, blood could be pulled from a patient and OSR orother compounds added to that blood before being returned to thepatient.

The compositions and methods of the present invention may beaccomplished by various means which are illustrated in the examplesbelow. These examples are intended to be illustrative only as numerousmodifications and variations will be apparent to those skilled in theart.

EXAMPLE 1

In this example, 3.14 grams of 2-aminoethanethiol hydrochloride wasdissolved in chloroform, and 3.88 ml of triethylamine were added. 2.81grams of isophthaloyl chloride was then dissolved in chloroform undernitrogen. 2-aminoethanethiol hydrochloride and 1,3-isophthaloylchloride, prepared as described supra, were then slowly mixed, and theresulting solution was stirred under nitrogen in an ice bath for severalhours. The resulting solution was then filtered under nitrogen, andseveral water/chloroform extractions performed. Following removal ofexcess solvent by rotary evaporation or distillation, the resultingproduct was passed through a silica gel column using ethylacetate/chloroform. Excess solvent was removed by rotary evaporation andvacuum-drying, resulting in a white precipitate. The resulting 1,3benzene-thiol product had the formula:

where R is an alkyl thio chain containing two methyl groups coupledthrough the carboxyl by an amide linkage.

EXAMPLE 2

In this example, 2.76 grams of aminomethanethiol hydrochloride aredissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81grams of isophthaloyl chloride are then dissolved in chloroform undernitrogen. Aminomethanethiol hydrochloride and isophthaloyl chloride,prepared as described supra, are then slowly mixed, and the resultingsolution is stirred under nitrogen in an ice bath for several hours. Theresulting solution is then filtered under nitrogen, and severalwater/chloroform extractions are performed. Excess solvent is removed byrotary evaporation or distillation, and the resulting product is passedthrough a silica gel column using ethyl acetate/chloroform. Excesssolvent is removed by rotary evaporation and vacuum-drying, resulting ina white precipitate. The resulting 1,3 benzene-thiol product has theformula:

where R is an alkyl thiol chain containing one methyl group coupledthrough the carboxyl by an amide linkage.

EXAMPLE 3

This example, 3.53 grams of 3-aminopropanethiol hydrochloride aredissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81grams of isophthaloyl chloride are then dissolved in chloroform undernitrogen. 3-aminopropanethiol hydrochloride and isophthaloyl chloride,prepared as described supra, are then slowly mixed, and the resultingsolution is stirred under nitrogen in an ice bath for several hours. Theresulting solution is then filtered under nitrogen, and severalwater/chloroform extractions are performed. Excess solvent is removed byrotary evaporation or distillation, and the resulting product is passedthrough a silica gel column using ethyl acetate/chloroform. Excesssolvent is removed by rotary evaporation and vacuum-drying, resulting ina white precipitate. The resulting 1,3 benzene-thiol product has theformula:

where R is an alkyl thiol chain containing three methyl groups coupledthrough the carboxyl by an amide linkage.

EXAMPLE 4

In this example, 3.92 grams of 4-aminobutanethiol hydrochloride aredissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81grams of isophthaloyl chloride are then dissolved in chloroform undernitrogen. 4-aminobutanethiol hydrochloride and isophthaloyl chloride,prepared as described supra, are then slowly mixed, and the resultingsolution is stirred under nitrogen in an ice bath for several hours. Theresulting solution is then filtered under nitrogen, and severalwater/chloroform extractions are performed. Excess solvent is removed byrotary evaporation or distillation, and the resulting product is passedthrough a silica gel column using ethyl acetate/chloroform. Excesssolvent is removed by rotary evaporation and vacuum-drying, resulting ina white precipitate. The resulting 1,3 benzene-thiol product has theformula:

where R is an alkyl thiol chain containing four methyl groups coupledthrough the carboxyl by an amide linkage.

EXAMPLE 5

In this example, 5 grams of 2,6 pyridine dicarbonyl dichloride weredissolved in chloroform under nitrogen. 5.56 grams of 2-aminothioethanethiol hydrochloride were also dissolved in chloroform under nitrogen,and slowly added to the acid chloride solution in an ice bath.Approximately 13.66 ml of triethylamine were added. The resultingmixture was stirred under nitrogen for 2-4 hours. The resultingyellow/brown solution was filtered under nitrogen, extracted three timeswith water/chloroform, refiltered under nitrogen, and excess solvent wasremoved by rotary evaporation or distillation. The resulting product wasredissolved in chloroform and passed through a silica gel column using70% ethyl acetate/30% chloroform. The resulting white precipitate was a2,6 pyridine thiol product with the formula:

where R is an alkyl thiol chain containing two methyl groups coupledthrough the carboxyl by an amide linkage.

EXAMPLE 6

Effect of daily administration of OSR on key biochemical parameters.Table 6-1 shows that the redox ratio (GSH/GSSG) was dramaticallyimproved in 10 subjects taking 200 mg of OSR per day for a period ofapproximately 60 days. Improvement was seen in the first 30 days andcontinued into the second month. Also, the major improvement seemed toresult from the very significant decrease in oxidized glutathione (GSSG)instead of a total increase in all forms of glutathione. This would bebest explained by OSR scavenging hydroxyl free radicals salvaging theGSH by preventing its oxidation to GSSG. This change occurred in 10 of10 subjects.

TABLE 6-1 Effect of OSR on blood GSH, GSSG levels and GSH/GSSG ratios.tGSH/GSSG GSSG GSH Time (months) Patient # 0 1 2 0 1 2 0 1 2 1 40.3 53.687.1 0.133 0.129 0.065 5.4 6.9 5.7 2 42.9 37.5 87.7 0.159 0.209 0.1176.8 7.8 10.3 3 24.8 32.3 64.5 0.167 0.154 0.083 4.1 5.0 5.4 4 14.8 22.128.6 0.482 0.282 0.189 7.1 6.2 5.4 5 66.9 73.7 93.7 0.108 0.103 0.0677.2 7.6 6.3 6 14.1 33.4 38.5 0.308 0.154 0.137 4.3 5.2 5.3 7 36.9 40.344.9 0.127 0.113 0.081 4.7 4.6 3.6 8 17.3 36.2 28.7 0.236 0.146 0.1954.1 5.3 5.6 9 11.4 16.9 48.9 0.521 0.396 0.139 5.9 6.7 6.8 10 15.8 42.869.6 0.283 0.165 0.119 4.5 7.1 8.3 Average 28.5 38.9 59.2 0.252 0.1850.119 5.4 6.2 6.3

This data was collected from a single clinic where the subjects variedin age from 8 to 73 years old and were 5 male and 5 female. All were inreasonable health with no obvious bacterial infections. GSH/GSSG ratiosincreased in all primarily due to the drop in GSSG levels in allsubjects. GSH levels remained relatively constant and increased slightlyin 7 of 10. The average tGSH/GSSG ratio almost doubled caused by a nearaverage halving of the GSSG levels.

To determine if OSR changed the level of cysteine, the rate limitingamino acid in glutathione synthesis, the level of all thiol containingamino acids was done for the same 10 patients for a two month period. Asseen in Table 6-2, there was no significant change in the amino acidlevels for any of the patients with one exception. The homocysteinelevel was high in patient #9, a 72 year old male diagnosed withAlzheimer's disease, over the two month testing his levels dropped tonear normal levels. These results imply that OSR increases GSH levels byscavenging hydroxyl free radicals and salvaging GSH, not by supplyingmore cysteine for GSH synthesis.

TABLE 6-2 Effect of OSR on blood sulfur containing amino acid levels(cysteine, methionine, homocysteine). Cysteine Methionine HomocysteineTime (months) Patient # 0 1 2 0 1 2 0 1 2 AGE 1 200 212 202 14.8 15.416.4 4.63 5.51 5.31 8 wm 2 170 167 169 20.7 22.7 26.0 5.74 5.13 5.04 9wf 3 240 231 260 22.1 22.6 26.3 5.16 5.91 6.32 9 wf 4 237 250 185 22.119.4 30.9 7.92 8.36 9.18 11 wm 5 231 225 244 20.9 24.0 30.4 6.07 5.315.75 12 wm 6 269 217 248 16.02 16.4 32.0 9.95 8.61 6.18 32 wf 7 282 246251 23.5 26.6 27.2 7.26 7.45 8.78 45 wm 8 304 243 290 15.4 17.2 25.49.69 9.27 9.11 71 wf 9 344 255 317 20.5 28.3 31.2 21.2 13.9 12.8* 72male AD 10 288 253 324 21.1 23.1 33.7 11.4 12.6 16.1 73 wf

No significant consistent changes in cysteine, methionine orhomocysteine levels were observed. The possible exception was thehomocysteine levels in patient #9, a male with Alzheimer's disease.

As seen in Table 6-3, glutathione-S-transferase (GST) was consistentlyelevated in all 10 patients in this study after OSR treatment. GST is anenzyme that uses glutathione (GSH) as a substrate to covalently modifycertain organic toxins by ‘transferring GSH’ to a P-450 enzyme oxidizedsite on the toxin. This results in a GSH-toxin complex that is now watersoluble and capable of being excreted from the body. GST wasnon-detectable in all 10 patients at the start of the study and wasdetectable in all 10 patients at the end of the study. The change in theredox level most likely had something to do with the appearance of thisenzyme. It is a common mechanism in cellular regulation that thelowering of a substrate (e.g. glutathione) needed at several locationsresults in the suppressed expression of the enzyme (e.g. GST) that usethis substrate for reactions that are less necessary to supportsurvival. The buildup of GSH most likely induces the expression of GSTand this buildup accounts for the induction of new GST synthesis.

TABLE 6-3 Effect of OSR on Glutathione-S-transferase (GST) levels(ng/ml) GST Time (months) Patient # 0 1 2 1 L L 0.48 2 L L 0.48 3 L 0.460.43 4 L L 0.53 5 L L 0.43 6 L L 0.37 7 L L 0.32 8 L 0.58 0.43 9 L L0.63 10 L L 0.43 GST activities increased in every patient. Detectionlevels were 0.4 for normals to 3.1 for a high level for GST.

EXAMPLE 7

Protective effects of OSR on rats injected subcutaneously with mercuricchloride.

The mercury chloride LD 50 for rats is reported to be 3.2 mg/kg bodyweight intraperitoneal. Our experiments were designed around this value.

For each of the experiments nine, 5-7 weeks old, rats were chosen. Theywere divided into three groups and they were fed rat chow and water adlibitum.

The mercuric chloride was dissolved in PBS/DMSO and injectedintraperitoneally at time zero.

The compound OSR was dissolved in 0.75 ml DMSO and 0.25 ml PBS.Injection was subcutaneous under the skin covering the stomach. Thesewere done 20 min. after the injection of the mercuric chloride.

TABLE 7-1 Dosage of Mercury chloride at 2 mg/kg body weight. OSR GROUPCONTROL GROUP Rat 1 Rat 2 Rat 3 Rat 1 Rat 2 Rat 3 Weight (gram) 230 242238 237 242 246 Mercury chloride (mg)* 0.46 0.48 0.48 0.47 0.48 0.49OSR(mg)** 32.66 34.4 33.8 0 0 0  0 hr A A A A A A  6 hr A A A A A A 12hr A A A A A D 24 hr A A A D D — 48 hr A A A — — —  1 week A A A — — —*= Equivalent to 2 mg/kg body weight. **= Equivalent to 0.5millimoles/kg body weight D = Dead; A = Alive

TABLE 7-2 Dosage of mercury 14 mg/kg OSR GROUP CONTROL GROUP Rat 1 Rat 2rat 3 Rat 1 Rat 2 Rat 3 Weight (in gram) 229.0 243.0 242.0 243.0 238.0246.0 Mercury chloride *¹ 3.2 3.4 3.4 3.4 3.3 3.4 OSR(mg)*² 65.0 69.068.7 0.0 0.0 0.0  0 hr A A A A A A  6 hr A A A D D A 12 hr A A A — — D24 hr A A A — — — 48 hr D A A — — —  1 week — A A — — — *¹ = Equivalentto 14 mg/kg body weight. *²= Equivalent to 1 mM/kg body weight D = Dead;A = Alive

EXAMPLE 8

Mixture with oil. OSR may be admixed with emu oil or another oil nottypically used as a pharmaceutical-grade excipient but known in the artto be useful in the cosmetic and or non-allopathic medical arts, therebymaking an OSR-oil mixture useful as an antioxidant and/or detoxicant.

EXAMPLE 9

Functional food. OSR may be admixed with a food known in the art,thereby making an OSR-food mixture useful as an antioxidant ordetoxicant functional food.

EXAMPLE 10

Medicament useful for treating disease. A therapeutically effectivemedicament composition containing OSR may be administered orally to ahuman subject in whom it is desired to ameliorate the effect of anydisease known to be associated with oxidative stress, including withoutlimitation each disease listed in Chapter 9 of Halliwell and Gutteridge2007, op. cit. (Aspects of the relationship between oxidative stress andaging are discussed in Chapter 10 of that work.)

EXAMPLE 11

Medicament and/or preparation of dosage form. To prepare a medicamentand/or suitable dosage form, OSR may be admixed and/or contacted withone or more of the excipients listed in Table 11-1.

TABLE 11-1 Excipients Acacia Acesulfame Potassium Acetic Acid, GlacialAcetone Acetyltributyl Citrate Acetyltriethyl Citrate Agar AlbuminAlcohol Alginic Acid Aliphatic Polyesters Alitame Almond Oil AlphaTocopherol Aluminum Hydroxide Adjuvant Aluminum Oxide Aluminum PhosphateAdjuvant Aluminum Stearate Ammonia Solution Ammonium Alginate AscorbicAcid Ascorbyl Palmitate Aspartame Attapulgite Bentonite BenzalkoniumChloride Benzethonium Chloride Benzoic Acid Benzyl Alcohol BenzylBenzoate Boric Acid Bronopol Butylated Hydroxyanisole ButylatedHydroxytoluene Butylparaben Calcium Alginate Calcium Carbonate CalciumPhosphate, Dibasic Anhydrous Calcium Phosphate, Dibasic DihydrateCalcium Phosphate, Tribasic Calcium Stearate Calcium Sulfate Canola OilCarbomer Carbon Dioxide Carboxymethylcellulose CalciumCarboxymethylcellulose Sodium Carrageenan Castor Oil Castor Oil,Hydrogenated Cellulose, Microcrystalline Cellulose, Powdered Cellulose,Silicified Microcrystalline Cellulose Acetate Cellulose AcetatePhthalate Ceratonia Cetostearyl Alcohol Cetrimide Cetyl AlcoholCetylpyridinium Chloride Chitosan Chlorhexidine ChlorobutanolChlorocresol Chlorodifluoroethane (HCFC) Chlorofluorocarbons (CFC)Chloroxylenol Cholesterol Citric Acid Monohydrate Colloidal SiliconDioxide Coloring Agents Copovidone Corn Oil Cottonseed Oil CresolCroscarmellose Sodium Crospovidone Cyclodextrins CyclomethiconeDenatonium Benzoate Dextrates Dextrin Dextrose Dibutyl Phthalate DibutylSebacate Diethanolamine Diethyl Phthalate Difluoroethane (HFC)Dimethicone Dimethyl Ether Dimethyl Phthalate Dimethyl SulfoxideDimethylacetamide Disodium Edetate Docusate Sodium Edetic AcidErythorbic Acid Erythritol Ethyl Acetate Ethyl Lactate Ethyl MaltolEthyl Oleate Ethyl Vanillin Ethylcellulose Ethylene GlycolPalmitostearate Ethylene Vinyl Acetate Ethylparaben Fructose FumaricAcid Gelatin Glucose, Liquid Glycerin Glyceryl Behenate GlycerylMonooleate Glyceryl Monostearate Glyceryl Palmitostearate GlycofurolGuar Gum Hectorite Heptafluoropropane (HFC) Hexetidine Hydrocarbons (HC)Hydrochloric Acid Hydroxyethyl Cellulose Hydroxyethylmethyl CelluloseHydroxypropyl Cellulose Hydroxypropyl Cellulose, Low-substitutedHydroxypropyl Starch Hypromellose Hypromellose Acetate SuccinateHypromellose Phthalate Imidurea Inulin Iron Oxides Isomalt IsopropylAlcohol Isopropyl Myristate Isopropyl Palmitate Kaolin Lactic AcidLactitol Lactose, Anhydrous Lactose, Monohydrate Lactose, Spray-DriedLanolin Lanolin, Hydrous Lanolin Alcohols Lauric Acid Lecithin LeucineLinoleic Acid Macrogol 15 Hydroxystearate Magnesium Aluminum SilicateMagnesium Carbonate Magnesium Oxide Magnesium Silicate MagnesiumStearate Magnesium Trisilicate Malic Acid Maltitol Maltitol SolutionMaltodextrin Maltol Maltose Mannitol Medium-chain TriglyceridesMeglumine Menthol Methylcellulose Methylparaben Mineral Oil Mineral Oil,Light Mineral Oil and Lanolin Alcohols Monoethanolamine MonosodiumGlutamate Monothioglycerol Myristic Acid Neohesperidin DihydrochalconeNitrogen Nitrous Oxide Octyldodecanol Oleic Acid Oleyl Alcohol Olive OilPalmitic Acid Paraffin Peanut Oil Pectin Petrolatum and Lanolin AlcoholsPetrolatum Phenol Phenoxyethanol Phenylethyl Alcohol PhenylmercuricAcetate Phenylmercuric Borate Phenylmercuric Nitrate Phosphoric AcidPolacrilin Potassium Poloxamer Polycarbophil Polydextrose PolyethyleneGlycol Polyethylene Oxide Polymethacrylates Poly(methyl vinylether/maleic anhydride) Polyoxyethylene Alkyl Ethers PolyoxyethyleneCastor Oil Derivatives Polyoxyethylene Sorbitan Fatty Acid EstersPolyoxyethylene Stearates Polyvinyl Acetate Phthalate Polyvinyl AlcoholPotassium Alginate Potassium Benzoate Potassium Bicarbonate PotassiumChloride Potassium Citrate Potassium Hydroxide Potassium MetabisulfitePotassium Sorbate Povidone Propionic Acid Propyl Gallate PropyleneCarbonate Propylene Glycol Propylene Glycol Alginate Propylparaben2-Pyrrolidone Raffinose Saccharin Saccharin Sodium Saponite Sesame OilShellac Simethicone Sodium Acetate Sodium Alginate Sodium AscorbateSodium Benzoate Sodium Bicarbonate Sodium Borate Sodium Chloride SodiumCitrate Dihydrate Sodium Cyclamate Sodium Hyaluronate Sodium HydroxideSodium Lactate Sodium Lauryl Sulfate Sodium Metabisulfite SodiumPhosphate, Dibasic Sodium Phosphate, Monobasic Sodium Propionate SodiumStarch Glycolate Sodium Stearyl Fumarate Sodium Sulfite Sorbic AcidSorbitan Esters (Sorbitan Fatty Acid Esters) Sorbitol Soybean Oil StarchStarch, Pregelatinized Starch, Sterilizable Maize Stearic Acid StearylAlcohol Sucralose Sucrose Sugar, Compressible Sugar, Confectioner'sSugar Spheres Sulfobutylether β-Cyclodextrin Sulfuric Acid Sunflower OilSuppository Bases, Hard Fat Talc Tartaric Acid Tetrafluoroethane (HFC)Thaumatin Thymol Titanium Dioxide Tragacanth Trehalose TriacetinTributyl Citrate Triethanolamine Triethyl Citrate Vanillin VegetableOil, Hydrogenated Water Wax, Anionic Emulsifying Wax, Carnauba Wax,Cetyl Esters Wax, Microcrystalline Wax, Nonionic Emulsifying Wax, WhiteWax, Yellow Xanthan Gum Xylitol Zein Zinc Acetate Zinc Stearate

EXAMPLE 12

Dosage form. A suitable dosage form for administration of OSR or otheractive compound may be chosen from among the dosage forms listed inTable 12-1.

TABLE 12-1 Dosage forms NAME DEFINITION AEROSOL A product that ispackaged under pressure and contains therapeutically active ingredientsthat are released upon activation of an appropriate valve system; it isintended for topical application to the skin as well as localapplication into the nose (nasal aerosols), mouth (lingual aerosols), orlungs (inhalation aerosols). AEROSOL, A product that is packaged underpressure and POWDER contains therapeutically active ingredients, in theform of a powder, that are released upon activation of an appropriatevalve system. BAR, CHEWABLE A solid dosage form usually in the form of arectangle that is meant to be chewed. CAPSULE A solid oral dosage formconsisting of a shell and a filling. The shell is composed of a singlesealed enclosure, or two halves that fit together and which aresometimes sealed with a band. Capsule shells may be made from gelatin,starch, or cellulose, or other suitable materials, may be soft or hard,and are filled with solid or liquid ingredients that can be poured orsqueezed. CAPSULE, COATED A solid dosage form in which the drug isenclosed within either a hard or soft soluble container or “shell” madefrom a suitable form of gelatin; additionally, the capsule is covered ina designated coating. CAPSULE, COATED A solid dosage form in which thedrug is PELLETS enclosed within either a hard or soft soluble containeror “shell” made from a suitable form of gelatin; the drug itself is inthe form of granules to which varying amounts of coating have beenapplied. CAPSULE, COATED, A solid dosage form in which the drug isEXTENDED enclosed within either a hard or soft soluble RELEASE containeror “shell” made from a suitable form of gelatin; additionally, thecapsule is covered in a designated coating, and which releases a drug(or drugs) in such a manner to allow at least a reduction in dosingfrequency as compared to that drug (or drugs) presented as aconventional dosage form. CAPSULE, DELAYED A solid dosage form in whichthe drug is RELEASE enclosed within either a hard or soft solublecontainer made from a suitable form of gelatin, and which releases adrug (or drugs) at a time other than promptly after administration.Enteric-coated articles are delayed release dosage forms. CAPSULE,DELAYED A solid dosage form in which the drug is RELEASE PELLETSenclosed within either a hard or soft soluble container or “shell” madefrom a suitable form of gelatin; the drug itself is in the form ofgranules to which enteric coating has been applied, thus delayingrelease of the drug until its passage into the intestines. CAPSULE, Asolid dosage form in which the drug is EXTENDED enclosed within either ahard or soft soluble RELEASE container made from a suitable form ofgelatin, and which releases a drug (or drugs) in such a manner to allowa reduction in dosing frequency as compared to that drug (or drugs)presented as a conventional dosage form. CAPSULE, FILM A solid dosageform in which the drug is COATED, enclosed within either a hard or softsoluble EXTENDED container or “shell” made from a suitable form RELEASEof gelatin; additionally, the capsule is covered in a designated filmcoating, and which releases a drug (or drugs) in such a manner to allowat least a reduction in dosing frequency as compared to that drug (ordrugs) presented as a conventional dosage form. CAPSULE, GELATIN A soliddosage form in which the drug is COATED enclosed within either a hard orsoft soluble container made from a suitable form of gelatin; through abanding process, the capsule is coated with additional layers of gelatinso as to form a complete seal. CAPSULE, LIQUID A solid dosage form inwhich the drug is FILLED enclosed within a soluble, gelatin shell whichis plasticized by the addition of a polyol, such as sorbitol orglycerin, and is therefore of a somewhat thicker consistency than thatof a hard shell capsule; typically, the active ingredients are dissolvedor suspended in a liquid vehicle. CONCENTRATE A liquid preparation ofincreased strength and reduced volume which is usually diluted prior toadministration. CORE, EXTENDED An ocular system placed in the eye fromwhich RELEASE the drug diffuses through a membrane at a constant rateover a specified period. CREAM An emulsion, semisolid³ dosage form,usually containing >20% water and volatiles⁵ and/or <50% hydrocarbons,waxes, or polyols as the vehicle. This dosage form is generally forexternal application to the skin or mucous membranes. CREAM, A creamdosage form that enhances drug AUGMENTED delivery. Augmentation does notrefer to the strength of the drug in the dosage form. NOTE: CDER hasdecided to refrain from expanding the use of this dosage form due todifficulties in setting specific criteria that must be met to beconsidered “augmented”. DRUG DELIVERY Modern technology, distributedwith or as a part SYSTEM of a drug product that allows for the uniformrelease or targeting of drugs to the body. ELIXIR A clear, pleasantlyflavored, sweetened hydroalcoholic liquid containing dissolved medicinalagents; it is intended for oral use. EMULSION A dosage form consistingof a two-phase system comprised of at least two immiscible liquids^(l),one of which is dispersed as droplets (internal or dispersed phase)within the other liquid (external or continuous phase), generallystabilized with one or more emulsifying agents. (Note: Emulsion is usedas a dosage form term unless a more specific term is applicable, e.g.cream, lotion, ointment.) ENEMA A rectal preparation for therapeutic,diagnostic, or nutritive purposes. EXTRACT A concentrated preparation ofvegetable or animal drugs obtained by removal of the active constituentsof the respective drugs with a suitable menstrua, evaporation of all ornearly all of the solvent, and adjustment of the residual masses orpowders to the prescribed standards. FIBER, EXTENDED A slender andelongated solid thread-like RELEASE substance that delivers drug in sucha manner to allow a reduction in dosing frequency as compared to thatdrug (or drugs) presented as a conventional dosage form. FILM, SOLUBLE Athin layer or coating which is susceptible to being dissolved when incontact with a liquid. FOR SOLUTION A product, usually a solid, intendedfor solution prior to administration. FOR SUSPENSION A product, usuallya solid, intended for suspension prior to administration. FORSUSPENSION, A product, usually a solid, intended for EXTENDED suspensionprior to administration; once the RELEASE suspension is administered,the drug will be released at a constant rate over a specified period.GEL A semisolid³ dosage form that contains a gelling agent to providestiffness to a solution or a colloidal dispersion.⁴ A gel may containsuspended particles. GLOBULE Also called pellets or pilules, are made ofpure sucrose, lactose, or other polysaccharides. They are formed intosmall globular masses of various sizes, and are medicated by placingthem in a vial and adding the liquid drug attenuation in the proportionnot less than one percent (v/w). After shaking, the medicated globulesare dried at temperatures not to exceed 40 degrees Centigrade. GRANULE Asmall particle or grain. GRANULE, A small medicinal particle or grain towhich an DELAYED enteric or other coating has been applied, thus RELEASEdelaying release of the drug until its passage into the intestines.GRANULE, A small particle or grain containing a medicinal EFFERVESCENTagent in a dry mixture usually composed of sodium bicarbonate, citricacid, and tartaric acid which, when in contact with water, has thecapability to release gas, resulting in effervescence. GRANULE, FOR Asmall medicinal particle or grain made SOLUTION available in its morestable dry form, to be reconstituted with solvent just beforedispensing; the granules are so prepared to contain not only themedicinal agent, but the colorants, flavorants, and any other desiredpharmaceutic ingredient. GRANULE, FOR A small medicinal particle orgrain made SUSPENSION available in its more stable dry form, to bereconstituted with solvent just before dispensing to form a suspension;the granules are so prepared to contain not only the medicinal agent,but the colorants, flavorants, and any other desired pharmaceuticingredient. GRANULE, FOR A small medicinal particle or grain madeSUSPENSION, available in its more stable dry form, to be EXTENDEDreconstituted with solvent just before dispensing RELEASE to form asuspension; the extended release system achieves slow release of thedrug over an extended period of time and maintains constant drug levelsin the blood or target tissue. INJECTABLE, An injection, which eitherconsists of or forms LIPOSOMAL liposomes (a lipid bilayer vesicleusually composed of phospholipids which is used to encapsulate an activedrug substance). INJECTION A sterile preparation intended for parenteraluse; five distinct classes of injections exist as defined by the USP.INJECTION, An emulsion consisting of a sterile, pyrogen- EMULSION freepreparation intended to be administered parenterally. INJECTION, LIPID[definition pending] COMPLEX INJECTION, A sterile preparation intendedfor reconstitution POWDER, to form a solution for parenteral use. FORSOLUTION INJECTION, A sterile preparation intended for reconstitutionPOWDER, to form a suspension for parenteral use. FOR SUSPENSIONINJECTION, A dried preparation intended for reconstitution to POWDER,form a suspension for parenteral use which has FOR SUSPENSION, beenformulated in a manner to allow at least a EXTENDED reduction in dosingfrequency as compared to RELEASE that drug presented as a conventionaldosage form (e.g., as a solution). INJECTION, A sterile freeze driedpreparation intended for POWDER, reconstitution for parenteral use whichhas been LYOPHILIZED, FOR formulated in a manner that would allowLIPOSOMAL liposomes (a lipid bilayer vesicle usually SUSPENSION composedof phospholipids which is used to encapsulate an active drug substance,either within a lipid bilayer or in an aqueous space) to be formed uponreconstitution. INJECTION, A liquid preparation, suitable for injection,which SUSPENSION, consists of an oil phase dispersed throughout anLIPOSOMAL aqueous phase in such a manner that liposomes (a lipid bilayervesicle usually composed of phospholipids which is used to encapsulatean active drug substance, either within a lipid bilayer or in an aqueousspace) are formed. INJECTION, A liquid preparation, suitable forinjection, which SUSPENSION, consists of solid particles dispersedthroughout a SONICATED liquid phase in which the particles are notsoluble. In addition, the product is sonicated while a gas is bubbledthrough the suspension, and this results in the formation ofmicrospheres by the solid particles. JELLY A class of gels, which aresemisolid systems that consist of suspensions made up of either smallinorganic particles or large organic molecules interpenetrated by aliquid--in which the structural coherent matrix contains a high portionof liquid, usually water. KIT A packaged collection of related material.LINIMENT A solution or mixture of various substances in oil, alcoholicsolutions of soap, or emulsions intended for external application.LIQUID, A liquid that delivers a drug in such a manner to EXTENDED allowa reduction in dosing frequency as RELEASE compared to that drug (ordrugs) presented as a conventional dosage form. LOTION An emulsion,liquid¹ dosage form. This dosage form is generally for externalapplication to the skin.² LOTION, A lotion dosage form that enhancesdrug delivery. AUGMENTED Augmentation does not refer to the strength ofthe drug in the dosage form. NOTE: CDER has decided to refrain fromexpanding the use of this dosage form due to difficulties in settingspecific criteria that must be met to be considered “augmented”. LOZENGEA solid preparation containing one or more medicaments, usually in aflavored, sweetened base which is intended to dissolve or disintegrateslowly in the mouth. A lollipop is a lozenge on a stick. MOUTHWASH Anaqueous solution which is most often used for its deodorant, refreshing,or antiseptic effect. OIL An unctuous, combustible substance which isliquid, or easily liquefiable, on warming, and is soluble in ether butinsoluble in water. Such substances, depending on their origin, areclassified as animal, mineral, or vegetable oils. OINTMENT A semisolid³dosage form, usually containing <20% water and volatiles⁵ and >50%hydrocarbons, waxes, or polyols as the vehicle. This dosage form isgenerally for external application to the skin or mucous membranes.OINTMENT, An ointment dosage form that enhances drug AUGMENTED delivery.Augmentation does not refer to the strength of the drug in the dosageform. NOTE: CDER has decided to refrain from expanding the use of thisdosage form due to difficulties in setting specific criteria that mustbe met to be considered “augmented”. PASTE A semisolid³ dosage form,containing a large proportion (20-50%) of solids finely dispersed in afatty vehicle. This dosage form is generally for external application tothe skin or mucous membranes. PASTILLE An aromatic preparation, oftenwith a pleasing flavor, usually intended to dissolve in the mouth. PATCHA drug delivery system that often contains an adhesive backing that isusually applied to an external site on the body. Its ingredients eitherpassively diffuse from, or are actively transported from, some portionof the patch. Depending upon the patch, the ingredients are eitherdelivered to the outer surface of the body or into the body. A patch issometimes synonymous with the terms ‘extended release film’ and‘system’. PATCH, EXTENDED A drug delivery system in the form of a patchRELEASE that releases the drug in such a manner that a reduction indosing frequency compared to that drug presented as a conventionaldosage form (e.g., a solution or a prompt drug-releasing, conventionalsolid dosage form). PATCH, EXTENDED A drug delivery system in the formof a patch RELEASE, which is controlled by an electric current thatELECTRICALLY releases the drug in such a manner that a CONTROLLEDreduction in dosing frequency compared to that drug presented as aconventional dosage form (e.g., a solution or a prompt drug-releasing,conventional solid dosage form). PELLET A small sterile solid massconsisting of a highly purified drug (with or without excipients) madeby the formation of granules, or by compression and molding. PELLETS,COATED, A solid dosage form in which the drug itself is in EXTENDED theform of granules to which varying amounts RELEASE of coating have beenapplied, and which releases a drug (or drugs) in such a manner to allowa reduction in dosing frequency as compared to that drug (or drugs)presented as a conventional dosage form. PILL A small, round soliddosage form containing a medicinal agent intended for oraladministration. PLASTER Substance intended for external application madeof such materials and of such consistency as to adhere to the skin andattach to a dressing; plasters are intended to afford protection andsupport and/or to furnish an occlusion and macerating action and tobring medication into close contact with the skin. POULTICE A soft,moist mass of meal, herbs, seed, etc., usually applied hot in cloth thatconsists of gruel- like consistency. POWDER An intimate mixture of dry,finely divided drugs and/or chemicals that may be intended for internalor external use. POWDER, FOR An intimate mixture of dry, finely divideddrugs SOLUTION and/or chemicals, which, upon the addition of suitablevehicles, yields a solution. POWDER, FOR An intimate mixture of dry,finely divided drugs SUSPENSION and/or chemicals, which, upon theaddition of suitable vehicles, yields a suspension (a liquid preparationcontaining the solid particles dispersed in the liquid vehicle). SALVE Athick ointment or cerate (a fat or wax based preparation with aconsistency between an ointment and a plaster). SOLUTION A clear,homogeneous liquid¹ dosage form that contains one or more chemicalsubstances dissolved in a solvent or mixture of mutually misciblesolvents. SOLUTION, A liquid preparation (i.e., a substance that flowsCONCENTRATE readily in its natural state) that contains a drug dissolvedin a suitable solvent or mixture of mutually miscible solvents; the drughas been strengthened by the evaporation of its nonactive parts.SOLUTION, FOR A solution for the preparation of an iced saline SLUSHslush, which is administered by irrigation and used to induce regionalhypothermia (in conditions such as certain open heart and kidneysurgical procedures) by its direct application. SOLUTION, GEL Asolution, which after usually being FORMING/DROPS administered in adrop-wise fashion, forms a gel. SOLUTION, GEL A solution that forms agel when it comes in FORMING, contact with ocular fluid, and whichallows at EXTENDED least a reduction in dosing frequency. RELEASESOLUTION/ DROPS A solution which is usually administered in a drop-wisefashion. SUPPOSITORY A solid body of various weights and shapes, adaptedfor introduction into the rectal orifice of the human body; they usuallymelt, soften, or dissolve at body temperature. SUPPOSITORY, A drugdelivery system in the form of a EXTENDED suppository that allows for areduction in dosing RELEASE frequency. SUSPENSION A liquidl dosage formthat contains solid particles dispersed in a liquid vehicle. SUSPENSION,A liquid preparation consisting of solid particles EXTENDED dispersedthroughout a liquid phase in which the RELEASE particles are notsoluble; the suspension has been formulated in a manner to allow atleast a reduction in dosing frequency as compared to that drug presentedas a conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form). SUSPENSION/DROPS Asuspension which is usually administered in a dropwise fashion. SYRUP Anoral solution containing high concentrations of sucrose or other sugars;the term has also been used to include any other liquid dosage formprepared in a sweet and viscid vehicle, including oral suspensions.TABLET A solid dosage form containing medicinal substances with orwithout suitable diluents. TABLET, A solid dosage form containingmedicinal CHEWABLE substances with or without suitable diluents that isintended to be chewed, producing a pleasant tasting residue in the oralcavity that is easily swallowed and does not leave a bitter orunpleasant after-taste. TABLET, COATED A solid dosage form that containsmedicinal substances with or without suitable diluents and is coveredwith a designated coating. TABLET, A solid dosage form containing aconglomerate COATED PARTICLES of medicinal particles that have each beencovered with a coating. TABLET, DELAYED A solid dosage form whichreleases a drug (or RELEASE drugs) at a time other than promptly afteradministration. Enteric-coated articles are delayed release dosageforms. TABLET, DELAYED A solid dosage form containing a conglomerateRELEASE of medicinal particles that have been covered PARTICLES with acoating which releases a drug (or drugs) at a time other than promptlyafter administration. Enteric-coated articles are delayed release dosageforms. TABLET, A tablet that, prior to administration, is intendedDISPERSIBLE to be placed in liquid, where its contents will bedistributed evenly throughout that liquid. Note: The term ‘tablet,dispersible’ is no longer used for approved drug products, and it hasbeen replaced by the term ‘tablet, for suspension’. TABLET, A soliddosage form containing mixtures of acids EFFERVESCENT (e.g., citricacid, tartaric acid) and sodium bicarbonate, which release carbondioxide when dissolved in water; it is intended to be dissolved ordispersed in water before administration. TABLET, EXTENDED A soliddosage form containing a drug which RELEASE allows at least a reductionin dosing frequency as compared to that drug presented in conventionaldosage form. TABLET, FILM A solid dosage form that contains medicinalCOATED substances with or without suitable diluents and is coated with athin layer of a water-insoluble or water-soluble polymer. TABLET, FILM Asolid dosage form that contains medicinal COATED, substances with orwithout suitable diluents and EXTENDED is coated with a thin layer of awater-insoluble or RELEASE water-soluble polymer; the tablet isformulated in such manner as to make the contained medicament availableover an extended period of time following ingestion. TABLET, FOR Atablet that forms a solution when placed in a SOLUTION liquid. TABLET,FOR A tablet that forms a suspension when placed in a SUSPENSION liquid(formerly referred to as a ‘dispersible tablet’). TABLET, A solid dosageform containing medicinal MULTILAYER substances that have beencompressed to form a multiple-layered tablet or atablet-within-a-tablet, the inner tablet being the core and the outerportion being the shell. TABLET, A solid dosage form containingmedicinal MULTILAYER, substances that have been compressed to form aEXTENDED multiple-layered tablet or a tablet-within-a-tablet, RELEASEthe inner tablet being the core and the outer portion being the shell,which, additionally, is covered in a designated coating; the tablet isformulated in such manner as to allow at least a reduction in dosingfrequency as compared to that drug presented as a conventional dosageform. TABLET, ORALLY A solid dosage form containing medicinalDISINTEGRATING substances which disintegrates rapidly, usually within amatter of seconds, when placed upon the tongue. TABLET, ORALLY A soliddosage form containing medicinal DISINTEGRATING, substances whichdisintegrates rapidly, usually DELAYED RELEASE within a matter ofseconds, when placed upon the tongue, but which releases a drug (ordrugs) at a time other than promptly after administration. TABLET,SOLUBLE A solid dosage form that contains medicinal substances with orwithout suitable diluents and possesses the ability to dissolve influids. TABLET, SUGAR A solid dosage form that contains medicinal COATEDsubstances with or without suitable diluents and is coated with acolored or an uncolored water- soluble sugar. Footnotes: ¹A liquid ispourable; it flows and conforms to its container at room temperature. Itdisplays Newtonian or pseudoplastic flow behavior. ²Previously thedefinition of a lotion was “The term lotion has been used to categorizemany topical suspensions, solutions, and emulsions intended forapplication to the skin.” The current definition of a lotion isrestricted to an emulsion. ³A semisolid is not pourable; it does notflow or conform to its container at room temperature. It does not flowat low shear stress and generally exhibits plastic flow behavior. ⁴Acolloidal dispersion is a system in which particles of colloidaldimension (i.e., typically between 1 nm and 1 μm) are distributeduniformly throughout a liquid. ⁵Percent water and volatiles are measuredby a loss on drying test in which the sample is heated at 105° C. untilconstant weight is achieved.

EXAMPLE 13

Route of administration. A suitable route of administration for a dosageform containing OSR may be chosen from among those listed in Table 13-1.

TABLE13-1 Routes of administration NAME DEFINITION BUCCAL Administrationdirected toward the cheek, generally from within the mouth. CONJUNCTIVALAdministration to the conjunctiva, the delicate membrane that lines theeyelids and covers the exposed surface of the eyeball. CUTANEOUSAdministration to the skin. ENDOSINUSIAL Administration within the nasalsinuses of the head. ENTERAL Administration directly into theintestines. EPIDURAL Administration upon or over the dura mater.EXTRACORPOREAL Administration outside of the body. HEMODIALYSISAdministration through hemodialysate fluid. INFILTRATION Administrationthat results in substances passing into tissue spaces or into cells.INTERSTITIAL Administration to or in the interstices of a tissue.INTRA-ABDOMINAL Administration within the abdomen. INTRA-ARTERIALAdministration within an artery or arteries. INTRA-ARTICULARAdministration within a joint. INTRACARTILAGINOUS Administration withina cartilage; endochondral. INTRACAUDAL Administration within the caudaequina. INTRACORONARY Administration within the coronary arteries.INTRADERMAL Administration within the dermis. INTRADUCTAL Administrationwithin the duct of a gland. INTRADUODENAL Administration within theduodenum. INTRADURAL Administration within or beneath the dura.INTRAEPIDERMAL Administration within the epidermis. INTRAESOPHAGEALAdministration within the esophagus. INTRAGASTRIC Administration withinthe stomach. INTRAGINGIVAL Administration within the gingivae.INTRALYMPHATIC Administration within the lymph. INTRAMEDULLARYAdministration within the marrow cavity of a bone. INTRAMENINGEALAdministration within the meninges (the three membranes that envelopethe brain and spinal cord). INTRAMUSCULAR Administration within amuscle. INTRAOCULAR Administration within the eye. INTRAOVARIANAdministration within the ovary. INTRAPERICARDIAL Administration withinthe pericardium. INTRAPERITONEAL Administration within the peritonealcavity. INTRAPLEURAL Administration within the pleura. INTRAPULMONARYAdministration within the lungs or its bronchi. INTRASINALAdministration within the nasal or periorbital sinuses. INTRASPINALAdministration within the vertebral column. INTRASYNOVIAL Administrationwithin the synovial cavity of a joint. INTRATENDINOUS Administrationwithin a tendon. INTRATHECAL Administration within the cerebrospinalfluid at any level of the cerebrospinal axis, including injection intothe cerebral ventricles. INTRATHORACIC Administration within the thorax(internal to the ribs); synonymous with the term endothoracic.INTRATUMOR Administration within a tumor. INTRAUTERINE Administrationwithin the uterus. INTRAVASCULAR Administration within a vessel orvessels. INTRAVENOUS Administration within or into a vein or veins.INTRAVENOUS BOLUS Administration within or into a vein or veins all atonce. INTRAVENOUS DRIP Administration within or into a vein or veinsover a sustained period of time. INTRAVENTRICULAR Administration withina ventricle. INTRAVESICAL Administration within the bladder.INTRAVITREAL Administration within the vitreous body of the eye. NASALAdministration to the nose; administered by way of the nose. OPHTHALMICAdministration to the external eye. ORAL Administration to or by way ofthe mouth. OROPHARYNGEAL Administration directly to the mouth andpharynx. OTHER Administration is different from others on this list.PARENTERAL Administration by injection, infusion, or implantation.PERCUTANEOUS Administration through the skin. PERIARTICULARAdministration around a joint. PERIDURAL Administration to the outsideof the dura mater of the spinal cord.. PERINEURAL Administrationsurrounding a nerve or nerves. PERIODONTAL Administration around atooth. RECTAL Administration to the rectum. RESPIRATORY Administrationwithin the respiratory tract (INHALATION) by inhaling orally or nasallyfor local or systemic effect. SOFT TISSUE Administration into any softtissue. SUBCONJUNCTIVAL Administration beneath the conjunctiva.SUBCUTANEOUS Administration beneath the skin; hypodermic. Synonymouswith the term SUBDERMAL. SUBLINGUAL Administration beneath the tongue.SUBMUCOSAL Administration beneath the mucous membrane. TOPICALAdministration to a particular spot on the outer surface of the body.The E2B term TRANSMAMMARY is a subset of the term TOPICAL. TRANSDERMALAdministration through the dermal layer of the skin to the systemiccirculation by diffusion. TRANSMUCOSAL Administration across the mucosa.

The foregoing description of the preferred embodiments of the presentinvention have been presented for purposes of illustration anddescription. It is not intended to be exhaustive or to limit theinvention to the precise form disclosed. Obvious modifications orvariations are possible in light of the above teachings. The embodimentswere chosen and described to provide the best illustration of theprinciples of the invention and its practical application to therebyenable one of ordinary skill in the art to utilize the invention invarious embodiments and with various modifications as are suited to theparticular use contemplated. All such modifications and variations arewithin the scope of the invention as determined by the appended claimswhen interpreted in accordance with the breadth to which they arefairly, legally and equitably entitled. The drawings and preferredembodiments do not and are not intended to limit the ordinary meaning ofthe claims in their fair and broad interpretation in any way.

What is claimed:
 1. A method of relieving oxidative stress in a mammal,comprising: administering to said mammal a pharmaceutically effectiveamount of a compound having a chemical formula:

where n=1-4 and X is selected from the group consisting of hydrogen,lithium sodium, potassium, rubidium, cesium and francium.
 2. The methodof claim 1, including using oral administration.
 3. The method of claim1, including administering between about 0.5 and about 100 milligrams ofsaid compound per kilogram of said mammal's total body weight per day.4. The method of claim 1, including using transdermal administration. 5.The method of claim 1, including using nasal administration.
 6. Themethod of claim 1, including using administration by suppository.
 7. Themethod of claim 1, including using intravenous administration.
 8. Themethod of claim 1, including administering said compound with aprecursor of glutathione.
 9. The method of claim 8, including selectingsaid precursor of glutathione from a group consisting of cysteine,glycine, glutamate and combinations thereof.
 10. The method of claim 1,including administering said compound with a dietary supplement thatsupports glutathione synthesis.
 11. The method of claim 10, includingselecting said dietary supplement from a group consisting of wheyprotein, N-acetylcysteine, cysteine, glutathione, nicotine adeninedinucleotide (NAD⁺), reduced nicotine adenine dinucleotide (NADH),glycylcysteine (gly-cys), glutamylcysteine (glu-cys), and combinationsthereof.
 12. The method of claim 1, wherein said compound has thechemical formula:


13. The method of claim 12, including using oral administration.
 14. Themethod of claim 12, including administering between about 0.5 and about100 milligrams of said compound per kilogram of said mammal's total bodyweight per day.